Antibody‒drug conjugates with DHODH inhibitor as novel payload class for cancer and SARS-CoV-2 infection therapies

Available online 12 November 2025

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Despite remarkable achievements in antibody‒drug conjugates (ADCs), payloads remain limited. The identification of ADC payloads with novel mechanisms will increase therapeutic options and expand indications. Herein, we describe the use of dihydroorotate dehydrogenase inhibitors (DHODHi) as a novel payload class that provides highly potent ADCs for antitumor and antiviral therapies. Technical innovations include the development of stability-controllable linkers to meet the distinct requirements of acute viral infections and chronic tumor conditions. The antitumor ADC TH-C8H exhibited significant efficacy against gastric cancer in vivo as monotherapy and enhanced efficacy when combined with the ferroptosis inducer RSL3. The antiviral ADC HG-C3 showed broad-spectrum anti-SARS-CoV-2 activity in vitro and in vivo. Our study expands the types of ADC payloads and provides novel insights into the development of innovative broad-spectrum ADCs.

Graphical abstractNovel DHODHi-based ADCs exhibited broad-spectrum antitumor and antiviral activities by blocking DNA/RNA replication. And the innovation of stability-controllable linkers promoted this discovery.